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Journal Article > ResearchFull Text

Evaluation of hydroxychloroquine or chloroquine for the prevention of COVID-19 (COPCOV): A double-blind, randomised, placebo-controlled trial

PLOS Med. 12 September 2024; Volume 21 (Issue 9); e1004428.; DOI:10.1371/journal.pmed.1004428
Schilling WHK, Mukaka M, Callery JJ, Llewelyn MJ, Cruz CV,  et al.
PLOS Med. 12 September 2024; Volume 21 (Issue 9); e1004428.; DOI:10.1371/journal.pmed.1004428

BACKGROUND

Hydroxychloroquine (HCQ) has proved ineffective in treating patients hospitalised with Coronavirus Disease 2019 (COVID-19), but uncertainty remains over its safety and efficacy in chemoprevention. Previous chemoprevention randomised controlled trials (RCTs) did not individually show benefit of HCQ against COVID-19 and, although meta-analysis did suggest clinical benefit, guidelines recommend against its use.


METHODS AND FINDINGS

Healthy adult participants from the healthcare setting, and later from the community, were enrolled in 26 centres in 11 countries to a double-blind, placebo-controlled, randomised trial of COVID-19 chemoprevention. HCQ was evaluated in Europe and Africa, and chloroquine (CQ) was evaluated in Asia, (both base equivalent of 155 mg once daily). The primary endpoint was symptomatic COVID-19, confirmed by PCR or seroconversion during the 3-month follow-up period. The secondary and tertiary endpoints were: asymptomatic laboratory-confirmed Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection; severity of COVID-19 symptoms; all-cause PCR-confirmed symptomatic acute respiratory illness (including SARS-CoV-2 infection); participant reported number of workdays lost; genetic and baseline biochemical markers associated with symptomatic COVID-19, respiratory illness and disease severity (not reported here); and health economic analyses of HCQ and CQ prophylaxis on costs and quality of life measures (not reported here). The primary and safety analyses were conducted in the intention-to-treat (ITT) population. Recruitment of 40,000 (20,000 HCQ arm, 20,000 CQ arm) participants was planned but was not possible because of protracted delays resulting from controversies over efficacy and adverse events with HCQ use, vaccine rollout in some countries, and other factors. Between 29 April 2020 and 10 March 2022, 4,652 participants (46% females) were enrolled (HCQ/CQ n = 2,320; placebo n = 2,332). The median (IQR) age was 29 (23 to 39) years. SARS-CoV-2 infections (symptomatic and asymptomatic) occurred in 1,071 (23%) participants. For the primary endpoint the incidence of symptomatic COVID-19 was 240/2,320 in the HCQ/CQ versus 284/2,332 in the placebo arms (risk ratio (RR) 0.85 [95% confidence interval, 0.72 to 1.00; p = 0.05]). For the secondary and tertiary outcomes asymptomatic SARS-CoV-2 infections occurred in 11.5% of HCQ/CQ recipients and 12.0% of placebo recipients: RR: 0.96 (95% CI, 0.82 to 1.12; p = 0.6). There were no differences in the severity of symptoms between the groups and no severe illnesses. HCQ/CQ chemoprevention was associated with fewer PCR-confirmed all-cause respiratory infections (predominantly SARS-CoV-2): RR 0.61 (95% CI, 0.42 to 0.88; p = 0.009) and fewer days lost to work because of illness: 104 days per 1,000 participants over 90 days (95% CI, 12 to 199 days; p < 0.001). The prespecified meta-analysis of all published pre-exposure RCTs indicates that HCQ/CQ prophylaxis provided a moderate protective benefit against symptomatic COVID-19: RR 0.80 (95% CI, 0.71 to 0.91). Both drugs were well tolerated with no drug-related serious adverse events (SAEs). Study limitations include the smaller than planned study size, the relatively low number of PCR-confirmed infections, and the lower comparative accuracy of serology endpoints (in particular, the adapted dried blood spot method) compared to the PCR endpoint. The COPCOV trial was registered with ClinicalTrials.gov; number NCT04303507.


INTERPRETATION

In this large placebo-controlled, double-blind randomised trial, HCQ and CQ were safe and well tolerated in COVID-19 chemoprevention, and there was evidence of moderate protective benefit in a meta-analysis including this trial and similar RCTs.

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Journal Article > ProtocolFull Text

Gastroenteritis rehydration of children with severe acute malnutrition (GASTROSAM): A phase II randomised controlled trial: Trial protocol

Wellcome Open Res. 16 January 2024; Volume 6; 160.; DOI:10.12688/wellcomeopenres.16885.2
Olupot-Olupot P, Aloroker F, Mpoya A, Mnjalla H, Paasi G,  et al.
Wellcome Open Res. 16 January 2024; Volume 6; 160.; DOI:10.12688/wellcomeopenres.16885.2

BACKGROUND

Children hospitalised with severe acute malnutrition (SAM) are frequently complicated (>50%) by diarrhoea ( ≥3 watery stools/day) which is accompanied by poor outcomes. Rehydration guidelines for SAM are exceptionally conservative and controversial, based upon expert opinion. The guidelines only permit use of intravenous fluids for cases with advanced shock and exclusive use of low sodium intravenous and oral rehydration solutions (ORS) for fear of fluid and/or sodium overload. Children managed in accordance to these guidelines have a very high mortality. The proposed GASTROSAM trial will reappraise current recommendations with mortality as the primary outcome. We hypothesize that liberal rehydration strategies for both intravenous and oral rehydration in SAM children with diarrhoea may reduce adverse outcomes.


METHODS

An open Phase II trial, with a partial factorial design, enrolling children in Uganda, Kenya, Nigeria and Niger aged 6 months to 12 years with SAM hospitalised with gastroenteritis (>3 loose stools/day) and signs of moderate and severe dehydration. In Stratum A (severe dehydration) children will be randomised (1:1:2) to WHO plan C (100mls/kg Ringers Lactate (RL) with intravenous rehydration (IV) given over 3-6 hours according to age including boluses for shock), slow rehydration (100 mls/kg RL over 8 hours (no boluses)) or WHO SAM rehydration regime (ORS only (boluses for shock (standard of care)). Stratum B incorporates all children with moderate dehydration and severe dehydration post-intravenous rehydration and compares (1:1 ratio) standard WHO ORS given for non-SAM (experimental) versus WHO SAM-recommended low-sodium ReSoMal. The primary outcome for intravenous rehydration is mortality to 96 hours and for oral rehydration a change in sodium levels at 24 hours post-randomisation. Secondary outcomes include measures assessing safety (evidence of pulmonary oedema or heart failure); change in sodium from post-iv levels for those in Stratum A; perturbations of electrolyte abnormalities (severe hyponatraemia <125 mmols/L or hypokalaemia.


DISCUSSION

If the trial shows that rehydration strategies for non-malnourished children are safe and improve mortality in SAM this could prompt revisions to the current treatment recommendations or may prompt future Phase III trials.


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Journal Article > ResearchFull Text

A global core outcome measurement set for snakebite clinical trials

Lancet Global Health. 1 February 2023; Volume 11 (Issue 2); e296-e300.; DOI:10.1016/S2214-109X(22)00479-X
Abouyannis M, Esmail H, Hamaluba M, Ngama M, Mwangudzah H,  et al.
Lancet Global Health. 1 February 2023; Volume 11 (Issue 2); e296-e300.; DOI:10.1016/S2214-109X(22)00479-X
Snakebite clinical trials have often used heterogeneous outcome measures and there is an urgent need for standardisation. A globally representative group of key stakeholders came together to reach consensus on a globally relevant set of core outcome measurements. Outcome domains and outcome measurement instruments were identified through searching the literature and a systematic review of snakebite clinical trials. Outcome domains were shortlisted by use of a questionnaire and consensus was reached among stakeholders and the patient group through facilitated discussions and voting. Five universal core outcome measures should be included in all future snakebite clinical trials-mortality, WHO disability assessment scale, patient-specific functional scale, acute allergic reaction by Brown criteria, and serum sickness by formal criteria. Additional syndrome-specific core outcome measures should be used depending on the biting species. This core outcome measurement set provides global standardisation, supports the priorities of patients and clinicians, enables meta-analysis, and is appropriate for use in low-income and middle-income settings.More
Journal Article > ResearchFull Text

Définition d'un jeu universel de critères de décision de base pour les essais cliniques sur les morsures de serpent

Med Trop Sante Int MTSI MTSI bulletin MTSI magazine MTSI-Revue Médecine tropicale et santé internationale. Bulletin Médecine tropicale et santé internationale. Magazine MTSI, la revue de la Société francophone de médecine tropicale et santé internationale. 1 February 2023; Volume 3 (Issue 3); DOI:10.48327/mtsi.v3i3.2023.421
Abouyannis M, Esmail H, Hamaluba M, Ngama M, Mwangudzah H,  et al.
Med Trop Sante Int MTSI MTSI bulletin MTSI magazine MTSI-Revue Médecine tropicale et santé internationale. Bulletin Médecine tropicale et santé internationale. Magazine MTSI, la revue de la Société francophone de médecine tropicale et santé internationale. 1 February 2023; Volume 3 (Issue 3); DOI:10.48327/mtsi.v3i3.2023.421
English
Français
CONTEXTE
Les essais cliniques sur les morsures de serpent ont souvent utilisé des critères de décision hétérogènes qui demandent à être standardisés.

MÉTHODE
Un groupe d'acteurs clés mondialement représentatifs s'est réuni pour parvenir à un consensus sur un jeu universel de critères de décision de base. Les domaines d'intérêt et les instruments d'évaluation des critères de décision ont été identifiés à partir d'une recherche documentaire et d'un examen systématique des essais cliniques concernant les envenimations par morsure de serpent. Les domaines d'intérêt ont été présélectionnés à l'aide d'un questionnaire et un consensus a été obtenu entre le groupe d'acteurs et un groupe représentatif de patients à la suite de discussions orientées et d'un vote.

RÉSULTATS
Cinq critères de décision de base universels devraient être inclus dans tous les futurs essais cliniques sur les morsures de serpent : la mortalité, l'échelle d'évaluation du handicap de l'OMS, l'échelle fonctionnelle propre à chaque patient, la réaction allergique immédiate selon les critères de Brown et la maladie sérique en fonction de critères formels. D'autres critères de décision spécifiques aux différents syndromes observés lors des envenimations par morsure de serpent doivent être utilisés en fonction de l'espèce responsable de la morsure.

CONCLUSION
Ce jeu universel de critères de décision de base permet une standardisation mondiale, répond aux priorités des patients et des cliniciens, favorise des méta-analyses et est compatible avec une utilisation dans les pays à revenu faible ou intermédiaire.
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Journal Article > ResearchFull Text

Immunogenicity and safety of fractional doses of yellow fever vaccines: a randomised, double-blind, non-inferiority trial

Lancet. 9 January 2021; Volume 397; DOI:10.1016/S0140-6736(20)32520-4
Juan-Giner A, Kimathi D, Grantz KH, Hamaluba M, Kazooba P,  et al.
Lancet. 9 January 2021; Volume 397; DOI:10.1016/S0140-6736(20)32520-4
BACKGROUND
Stocks of yellow fever vaccine are insufficient to cover exceptional demands for outbreak response. Fractional dosing has shown efficacy, but evidence is limited to the 17DD substrain vaccine. We assessed the immunogenicity and safety of one-fifth fractional dose compared with standard dose of four WHO-prequalified yellow fever vaccines produced from three substrains.

METHODS
We did this randomised, double-blind, non-inferiority trial at research centres in Mbarara, Uganda, and Kilifi, Kenya. Eligible participants were aged 18–59 years, had no contraindications for vaccination, were not pregnant or lactating, had no history of yellow fever vaccination or infection, and did not require yellow fever vaccination for travel. Eligible participants were recruited from communities and randomly assigned to one of eight groups, corresponding to the four vaccines at standard or fractional dose. The vaccine was administered subcutaneously by nurses who were not masked to treatment, but participants and other study personnel were masked to vaccine allocation. The primary outcome was proportion of participants with seroconversion 28 days after vaccination. Seroconversion was defined as post-vaccination neutralising antibody titres at least 4 times pre-vaccination measurement measured by 50% plaque reduction neutralisation test (PRNT50). We defined non-inferiority as less than 10% decrease in seroconversion in fractional compared with standard dose groups 28 days after vaccination. The primary outcome was measured in the per-protocol population, and safety analyses included all vaccinated participants. This trial is registered with ClinicalTrials.gov, NCT02991495.

FINDINGS
Between Nov 6, 2017, and Feb 21, 2018, 1029 participants were assessed for inclusion. 69 people were ineligible, and 960 participants were enrolled and randomly assigned to vaccine manufacturer and dose (120 to Bio-Manguinhos-Fiocruz standard dose, 120 to Bio-Manguinhos-Fiocruz fractional dose, 120 to Chumakov Institute of Poliomyelitis and Viral Encephalitides standard dose, 120 to Chumakov Institute of Poliomyelitis and Viral Encephalitides fractional dose, 120 to Institut Pasteur Dakar standard dose, 120 to Institut Pasteur Dakar fractional dose, 120 to Sanofi Pasteur standard dose, and 120 to Sanofi Pasteur fractional dose). 49 participants had detectable PRNT50 at baseline and 11 had missing PRNT50 results at baseline or 28 days. 900 were included in the per-protocol analysis. 959 participants were included in the safety analysis. The absolute difference in seroconversion between fractional and standard doses by vaccine was 1·71% (95% CI -2·60 to 5·28) for Bio-Manguinhos-Fiocruz, -0·90% (–4·24 to 3·13) for Chumakov Institute of Poliomyelitis and Viral Encephalitides, 1·82% (–2·75 to 5·39) for Institut Pasteur Dakar, and 0·0% (–3·32 to 3·29) for Sanofi Pasteur. Fractional doses from all four vaccines met the non-inferiority criterion. The most common treatment-related adverse events were headache (22·2%), fatigue (13·7%), myalgia (13·3%) and self-reported fever (9·0%). There were no study-vaccine related serious adverse events.

INTERPRETATION
Fractional doses of all WHO-prequalified yellow fever vaccines were non-inferior to the standard dose in inducing seroconversion 28 days after vaccination, with no major safety concerns. These results support the use of fractional dosage in the general adult population for outbreak response in situations of vaccine shortage.
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